Cell death is generally classified into one of two forms, necrosis or apoptosis. Necrosis typically occurs in response to severe physiological or environmental insult. Cells dying by necrosis show a distinct pattern of cellular breakdown, which eventually results in cell autolysis. The resulting release of cellular contents can cause inflammation in the surrounding tissues, furthering cell injury. Apoptosis on the other hand is a controlled or programmed series of cellular events ultimately leading to cell death. It is a mechanism for an organism to remove unwanted cells and is an important part of normal physiology. The two most often cited examples of apoptosis are in fetal development and in immune cell development. However, excessive or insufficient apoptosis can play a role in disease. Diseases in which there is an excessive accumulation of cells and insufficient apoptosis include cancer, inflammatory disorders and autoimmune diseases. Disorders in which excessive apoptotic cell death has been observed include neurodegenerative conditions such as Alzheimer's and Parkinson's diseases and ischemic stroke, brain or myocardial diseases. Tissue damage following stroke or myocardial infarction is largely apoptotic and there is growing evidence that the inhibition of apoptosis following ischemic injury can lessen the tissue damage.
One of the most specific molecular markers for apoptosis is the activation of the family of cysteine-dependent aspartate proteases, which are known as caspases. At least 11 human caspases have been characterized and these can be subdivided into three groups based on homology and substrate specificity. Group I caspases including 1, 4, 5, appear to be predominately involved in inflammation. Group II caspases including 6, 8, 9 and 10, are initiators of apoptotic signaling and further caspase activation. Group III caspases, including 3 and 7, are predominantly effector enzymes responsible for degrading cellular substrates in a highly specific manner. Although the precise repertoire of caspases involved in ischemic neuronal cell death have not been fully elucidated, histochemical and biochemical data combine to show the presence of activated caspases from each class in adult ischemic brain (Chen et al., J. Neuroscience, 18: 4914-4928 (1998), Krupinski et al., Neurobiol. Dis. 7: 332-342 (2000), Benchoua et al., J. Neuroscience 21: 7127-7134 (2001), Namura et al., J. Neuroscience. 18: 3659-3668 (1998)).
The utility of a caspase inhibitor for the treatment of a number of mammalian diseases associated with an increase in cellular apoptosis has been demonstrated using peptidic caspase inhibitors. For example, in rodent models caspase inhibitors have been shown to reduce infart size and inhibit cardiomyocyte apoptosis after myocardial infarction, to reduce brain lesion volume and neurological deficit resulting from stroke, to reduce post traumatic apoptosis and neurological deficit in traumatic brain injury, to be effective in treating fulminant liver destruction and to improve survival after endotoxic shock. (Yaoita, et al., Circulation, 97: 276 (1998), Endres et al., J. Cerebral Blood Flow and Metabolism, 18: 238 (1998), Cheng, et al., J. Clin. Invest., 101: 1992 (1998); Yakovlev, et al., J. Neuroscience, 17: 7415 (1997), Rodriquez, et al., J. Exp. Med., 184: 2067 (1996), Grobmyer, et al., Mol. Med., 5: 585 (1999)).
A caspase inhibitor may provide utility for the treatment of osteoarthritis. A recent study demonstrated an increase in the level of the active form of caspase 3 in osteoarthritis chondrocytes. (Pelletier, et al., Arthritis & Rheumatism, 43 (6): 1290 (2000)). In osteoarthritis chondrocytes, the distribution of cells staining for caspase 3 was superimposable to that of cells undergoing apoptosis. The strong correlation between caspase 3 and apoptosis supports the notion that caspase 3 plays a role in chondrocyte apoptosis.
A chemical agent that can regulate the activity of the caspases in either a broad or a selective manner may be a useful therapeutic agent to treat diseases where an excessive or an insufficient level apoptosis is apparent. Of particular interest is treating ischemic diseases resulting in cerebral or myocardial injury such as stroke or as in the case of myocardial infarction. Since caspases are also implicated in the inflammatory process, a caspase modulator may be of therapeutic utility to treat inflammatory diseases, such as arthritis, cholangitis, colitis, encephalitis, endocerolitis, hepatitis and pancreatitis.